tbuckley/cabot-search huggingface dataset:
Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): A prospective, single-arm phase II trial.
Authors: Dongming Liu, Han Mu, Changfu Liu, Weihao Zhang, Yunlong Cui, Qiang Wu, Xiaolin Zhu, Feng Fang, Wei Zhang, Wenge Xing, Qiang Li, Tianqiang Song, Wei Lu, Huikai Li
Journal: Journal of Clinical Oncology (2022)

4073 Background: Sintilimab plus IBI305, a bevacizumab biosimilar, showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma. Hepatic arterial infusion chemotherapy is an intraarterial procedure that has been widely used in Asia, with high response rate. This trial was designed to assess the feasibility and efficacy of HAIC combined with sintilimab and IBI305 in advanced unresectable hepatocellular carcinoma. Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma, China liver cancer staging (CNLC) stage IIb-IIIb, no previous systemic treatment, Child-Pugh classification A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. Patients received FOLOFOX-HAIC, followed by intravenous sintilimab (200 mg every 3 weeks, four cycles) and intravenous IBI305 (7.5 mg/kg every 3 weeks, three cycles). The primary endpoint was objective response rate (ORR) per mRECIST. Secondary endpoint were surgical conversion rate, pCR rate and R0 resection rate. The study is registered with Clinicaltrials.gov: NCT05029973. Results: Between May, 2021 to Sep, 2021, a total of 30 eligible patients were enrolled: median age 54.5 years (range 37-73); M:F 27:3; CNLC stage IIb/IIIa/IIIb: 3/16/11; Child-Pugh class A/B: 28/2; ECOG PS 0/1: 26/4. There were 23(76.7%) patients with hepatitis B and 5(16.7%) with hepatitis C. The median tumor size was 8.75 cm (interquartile range [IQR], 4.9-10.5), 60.0% pts present vascular invasion, and 36.7% had extrahepatic metastasis. Of 30 pts evaluable for response, 20 (66.7%; 95% CI: 47.2%-82.7%) achieved confirmed partial response, and became eligible for surgical resection. Finally, 14 of them received surgical resection and all (100%) achieved R0 resection, 3 pts completed radiofrequency ablation (RAF), 3 pts refused resection or RFA. The pCR rate in the patients completed pathological examination was 52.6% (95% CI: 28.9%-75.6%). The most common TRAEs included hypertension (23.3%), rash (16.7%), and abnormal liver function (10.0%). No grade 3-4 TRAEs were observed. Of note, in patients received surgery, 1 developed grade 1 biliary fistula, 1 developed hepatic failure and finally lead to death Conclusions: HAIC Combined With sintilimab and IBI305 resulted in a promising ORR, R0 surgical conversion rate and pCR rate with a manageable safety for initial unresectable advanced hepatocellular carcinoma. Further follow-up is ongoing. Clinical trial information: NCT05029973.
Predicting CNS penetration of precision medicine therapies in oncology: A comparison of the CNS TAP tool and the BOILED-Egg computational model.
Authors: Gianni Walker, Andrea Flynn Franson, Manjunath Pai, Karthik Ravi, Holly Roberts, Allison Schepers, Carl Johannes Koschmann, Bernard L. Marini
Journal: Journal of Clinical Oncology (2022)

2062 Background: The number of available targeted therapies has vastly expanded in recent years; however, only a selection of such therapies achieve adequate central nervous system (CNS) penetration. The CNS Targeted Agent Prediction (CNS TAP) Tool was developed to aid in the selection of precision medicine therapies based on preclinical data, clinical data, patient-specific genomic data, and importantly, optimal blood brain barrier penetration. Using a standardized murine pharmacokinetic (PK) model, we sought to determine the concordance of CNS penetration prediction by the CNS TAP Tool compared to the SwissADME BOILED-Egg computational model. Methods: Eleven drugs were chosen based on the most commonly altered and targeted pathways by our CNS tumor board. Mice were injected individually with the compounds of interest and sacrificed at four different time points to quantify drug concentration via LC-MS in brain tissue and blood samples for PK analyses (1,2,4,7 hours). The percent brain penetration (AUC brain/plasma ) was compared to published human phase I PK data and pathway IC-50 to determine if agents were adequately CNS penetrant. These results were compared against the CNS TAP Tool and BOILED-Egg prediction of CNS penetrance. Results: All 11 drugs chosen (Table) demonstrated adequate CNS penetration, suggesting likely CNS efficacy. The CNS TAP Tool correctly predicted 10/11 agents (91% concordance), the lone exception being panobinostat. In contrast, the BOILED-Egg model only successfully predicted 3/11 agents (27%). When restricting the analysis to drugs with &gt;50% CNS penetration (ponatinib, panobinostat, and ONC-201), the BOILED-Egg model successfully predicted CNS penetration of all agents. Conclusions: The clinician-curated CNS TAP Tool more accurately predicted CNS penetration of precision medicine therapies than the BOILED-Egg computational model, which performed best for drugs that achieve extremely high CNS penetration. The resulting PK and CNS penetration data for all agents was utilized to update and refine the CNS TAP tool for future patient use. [Table: see text]
Real-world treatment patterns in von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC): Costs of tumor reduction procedures and their complications.
Authors: Murali Sundaram, Yan Song, Jonathan Freimark, Richard Berman, Ha Nguyen, James Signorovitch, Eric Jonasch
Journal: Journal of Clinical Oncology (2022)

4539 Background: VHL disease is an inherited condition associated with tumors in multiple organs; RCC may affect up to 70% of patients with VHL. Patients often need many tumor reduction procedures (TRP) to manage renal neoplasms. This study evaluated TRP treatment patterns, costs, and complications among patients with VHL-RCC. Methods: Using an algorithm based on VHL manifestations, patients with VHL were identified from the Optum Clinformatics claims database. Patients were then selected with a prior RCC diagnosis. Minimum continuous enrollment of 12 months before and 3 months after first observed RCC diagnosis was required. TRPs for RCC included nephrectomy, renal ablation, and cryotherapy. Time to first TRP from initial observed RCC diagnosis was estimated using Kaplan-Meier analysis. Mean hospitalization costs per TRP type were estimated. Costs associated with TRP complications were estimated via linear regression; the explanatory variable was the presence of a given complication. Short-term complications were evaluated for 4 weeks post-TRP; long-term ones were evaluated over 6 months. Renal function was evaluated using chronic kidney disease (CKD) stages before and after TRPs, using diagnosis codes and eGFR lab values. Results: 160 patients with VHL-RCC were identified; mean follow-up time was 34.1 months. 115 (71.8%) patients incurred ≥1 RCC TRP over their study period. 68.4% had a TRP in the first year after RCC diagnosis and 76.5% had TRPs by year 5. Of the 125 observed TRPs, 97 (77.6%) were nephrectomies and 28 (22.4%) were ablation/cryotherapy. The mean costs for nephrectomy were nominally higher vs. ablation/cryotherapy ($29,313 vs. $18,290). The most common short-term complications were respiratory related (20.8%) and vascular injury/anemia (13.6%). The most common long-term complications were CKD stage 1-5 (24.0%) and end-stage renal disease (chronic dialysis dependence) (4.0%). The most expensive complications were related to impaired renal function: acute renal failure ($21,013 over 4 weeks), CKD ($26,032 over 6 months) and end stage renal disease ($65,338 over 6 months). At baseline, the proportion of patients with a diagnosis of CKD ≥ stage 3 was similar between patients who had TRPs (n = 115) and those who did not have TRPs (n = 45): 24.3% and 24.4%, respectively. After the first TRP, the proportion of patients with CKD ≥ stage 3 increased from 24.3% to 41.7%. Conclusions: Patients with VHL-RCC incur a significant clinical and economic burden related to TRPs for managing their renal tumors. This is in addition to the burden that VHL-RCC patients incur from the management of other VHL tumors. This study underscores the need for novel effective therapies to prevent or delay the recurrence of VHL-related renal neoplasms to mitigate the burden of morbidity and long-term medical management related to VHL.
Baseline peripheral T-cell composition in relation to radiographic phenotypes of immune-related pneumonitis.
Authors: Brian S. Henick, Shoiab Bukhari, Robert Winchester, Ziyan Lin, Alireza Khodadad-Jamayran, Aristotelis Tsirigos, Shalom S. Lerrer, Kieran Adam, Mary M. Salvatore, Galina Lagos, Aliyah Pabani, Rohan Maniar, Steven L. Reiner, Matthew Dallos, Matthen Mathew, Naiyer A. Rizvi, Adam Mor
Journal: Journal of Clinical Oncology (2022)

2545 Background: Pneumonitis is one of the most morbid complications from immune checkpoint inhibitor (ICI) treatment, but pathogenic mechanisms are unclear and no biomarkers permit pre-treatment risk assessment. We sought to characterize peripheral T cell subsets of pneumonitis patients on the single cell level. Methods: Blood was collected before and during ICI treatment in 24 patients. Cells were processed for single cell RNA sequencing (scRNAseq) employing CITEseq methodology using multiplexed cell surface markers labelled with a cocktail of oligonucleotide-tagged Total-Seq anti-human antibodies against CD4, CD8, CD45RA and CD27 followed by Chromium 10X sequencing. Principal Component Analysis was performed with iCellR, K-nearest-neighbor-based Network graph drawing Layout, and PhenoGraph clustering to assign cell types. CT scans were performed per standard of care and were reviewed by an experienced thoracic radiologist. Results: Seven of 24 patients developed pneumonitis; 9 did not experience an immune-related adverse event, and the remainder experienced arthritis (4), thyroiditis (3), or neurotoxicity (1). Pneumonitis patients had expanded proportions of TH2 TCF7 + T cells at baseline as compared to the other patients. Radiographically, two patients’ pneumonitis manifested as Chronic Hypersensitivity Pneumonitis (CHP), and four had Organized Pneumonia (OP). At baseline, CHP patients had significantly lower levels of CD8 + TCM cells (CXCR3+), double-positive T cells, gamma-delta T cells, and higher levels of naïve-like CD4 + TN TCF7 + LEF1 + and CD4 + TH1/2 CXCR3 + GATA3 + cells compared to OP. Gene expression levels also distinguished between these radiographic phenotypes. Conclusions: The peripheral T cell composition of patients who developed pneumonitis was distinct from those who did not in our cohort and unique by radiographic manifestation, suggesting potential pathogenic mechanisms and a prelude to circulating predictive markers of ICI toxicity.
Anti-LAG-3 antibody LBL-007 in combination with toripalimab in patients with unresectable or metastatic melanoma: A phase Ⅰ, open-label, multicenter, dose escalation/expansion study.
Authors: Xue Bai, Mei Li, Xingxiang Pu, Ying Cheng, Jing Chen, Yu Jiang, Xue Chen, Jingjing Liu, Li Fan, Jun Guo, Lu Si
Journal: Journal of Clinical Oncology (2022)

9538 Background: LBL007 is a novel, fully human IgG4 monoclonal antibody targeting human Lymphocyte-activation gene3 (LAG-3). Dual inhibition of anti-programmed cell death protein 1 (PD-1) and LAG-3 is anticipated to synergistically increase immune response against tumor growth. Here we report the preliminary safety and efficacy of LBL-007 in combination with Toripalimab (an anti-PD-1 antibody has approved for treatment of melanoma in China) in patients (pts) with unresectable or metastatic melanoma. Methods: Pts with unresectable or metastatic melanoma with or without prior anti-PD-(L)1 therapy were enrolled. This trial comprised 2 parts, namely part 1 (dose escalation), pts received LBL-007 (0.25/1/3/6 mg/kg) /Toripalimab (3 mg/kg) both i.v., Q2W; and part 2 (expansion), pts received LBL-007 (3/6 mg/kg)/Toripalimab (3 mg/kg) both i.v., Q2W. The primary objective was safety, the second objectives included pharmacokinetics, pharmacodynamics and efficacy (per RECIST 1.1). Results: By Jan 2022, 37 pts (15 [40.5%] male, median age 59 [range 31-74] years, 9 pts [24.3%] with baseline LDH elevation, 18 [48.6%] with acral, 12 [32.4%] mucosal, 5 [13.5%] nonacral cutaneous, 2 [5.4%] primary site unknown) were enrolled, with 17 in part 1 and 20 in part 2. No dose-limiting toxicity was observed in part 1, and the MTD was not reached. Of all 37 pts, the most common treatment-emergent adverse events (TEAEs) included anemia (24.3%), creatine phosphokinase elevation (24.3%), hypothyroidism (21.6%), and aspartate aminotransferase elevation (21.6%). For 32 radiologically evaluable pts, ORR was 12.5%, DCR was 53.1%. In a preplanned subtype-specific analysis in anti-PD-(L)1 treatment-naïve pts, ORR was 27.3 % vs. 0%, and DCR was 81.8% vs. 50.0% in acral and mucosal melanoma subtypes, respectively. For anti-PD-(L)1-resistant pts (n = 11), DCR was 18.2%. Conclusions: LBL007/Toripalimab combination is well tolerated and promising efficacy in pts with unresectable or metastatic melanoma, especially in the acral type without prior anti-PD-(L)1 therapy. Clinical trial information: NCT04640545.
Prognostic factors and clinical outcomes in patients with upper tract urothelial carcinoma undergoing surgery: The Cleveland Clinic experience.
Authors: Ramsha Ahmed, Michael Sheu, Wei Wei, Moshe Chaim Ornstein, Timothy D. Gilligan, Danai Dima, Steven Campbell, Byron H Lee, Christopher Weight, Christopher Eing Wee, Omar Y. Mian, Jihad Kaouk, Georges-Pascal Haber, Shilpa Gupta
Journal: Journal of Clinical Oncology (2022)

4593 Background: Upper tract urothelial carcinoma (UTUC) is a rare and heterogeneous disease accounting for approximately 5-10% of UC. While tumor grade and stage are known prognostic factors, data on other factors affecting outcomes in UTUC patients (pts) undergoing surgery is scant. We studied effect of various clinical factors and treatment on outcomes in UTUC. Methods: This is a single-institution retrospective study of 607 pts with UTUC undergoing surgery (nephroureterectomy (NU) or ureterectomy (U)) between Jan 2000 and Dec 2020. We studied effect of demographics, clinicopathological features, tumor location, preoperative Neutrophil-to-Lymphocyte ratio (NLR) and Albumin-to-Globulin ratio (AGR) and use of neoadjuvant or adjuvant chemotherapy on overall survival (OS) and recurrence free survival (RFS). Results: Of the 607 pts 401 (66.06%) were males and 355 (58.48%) were &gt; 70 yrs; 232 pts (38.22%) had UTUC of renal pelvis, 242 (39.87%) of ureter and 133 (21.91%) of both. 542 pts (89.29%) underwent radical NU and 65 (10.71%) segmental U; 328 patients (54.04%) were diagnosed with muscle invasive UC (MIUC) ( &gt; / = pT2) and 276 (45.47%) with non-MIUC ( &lt; / = pT2). Only 51 (8.4%) pts had lymph node positive (N+) disease. Lymphovascular invasion (LVI) was identified in 163 (26.85%) and carcinoma- in-situ (CIS) in 163 (26.85%) pts. Surgical margins were positive in 92 pts (15.16%). Median NLR cutoff was 3.25 and AGR cutoff was 1.25 (dichotomized based on literature). 44 pts (7.2%) received Neoadjuvant chemotherapy and 49 pts (8%) received adjuvant chemotherapy. Tumor recurrence occurred in 216 pts (35.58%) of which 65% were at urothelial and 35% at non-urothelial sites. With median follow up of 35.2 mos, median OS was 82.69 mos and 5-yr OS rate was 60%; median RFS was 29.47 mos and 5-yr RFS rate was 40%. High grade, age &gt; / = 70 yrs, high NLR, low AGR, presence of LVI, positive margins, CIS, MIUC, N+ disease were associated with worse outcomes. Pts with only renal pelvis involvement had better OS. Conclusions: In this large, long term follow-up series of UTUC pts, we identified several prognostic factors besides grade and stage that impact outcomes. These findings warrant further validation for use in clinical practice. [Table: see text]
Effectiveness and safety of eribulin as a front-line treatment in advanced breast cancer patients in China: A prospective real-world study.
Authors: Jian-Li Zhao, Xiao-Xiao Dinglin, Ya-Ping Yang, Si-Min Luo, Yang-Yang Cai, Jie Chai, Dong-Geng Liu, Ying Wang, He-Rui Yao
Journal: Journal of Clinical Oncology (2022)

e13015 Background: Eribulin is a non-taxane microtubule inhibitor, which was approved for the third-line treatment of advanced breast cancer (ABC) in China in 2019. However, the efficacy and safety data of eribulin for the ABC in Chinese patients is lacking, whether as first, second, or third-line regimens. This study aimed to evaluate the clinical effectiveness, safety, and treatment pattern of eribulin in first to third-line settings in Chinese ABC patients. Methods: Patients with histologically confirmed advanced breast cancer, who previously received ≤2 lines of treatment for metastatic disease were enrolled. In HR+/HER2- ABC, eribulin monotherapy was used; in HER2+ ABC, eribulin plus anti-HER2 targeted therapy were used; in metastasis triple-negative breast cancer (mTNBC), eribulin plus immunotherapy/chemotherapy were used. Primary outcome was progression-free survival (PFS). Secondary outcomes included disease control rate (DCR) and safety. This study was approved by the SYSMH and SYSUCC Ethics Committee (approval No. 2020-KY-064). Results: Forty-seven patients were enrolled from 2021.1.1 to 2021.10.20, including 41 metastatic and 6 de novo ABC patients. Eribulin was used as first-line therapy in 12 (25.5%) patients, second-line therapy in 24 patients (51.1%), and third-line therapy in 11 (23.1%) patients. More than 90% of the patients did not receive gemcitabine or vinorelbine, and 30.0% of them did not receive anthracycline or taxane previously. DCR was 70.2%, as 24 cases (51.1%) had stable disease and 9 cases (19.1%) had complete or partial remission. In subgroup analysis, median PFSs of 9.6 (95% CI: 6.5-12.7), 7.1 (95%CI: 4.4-9.8), and 5.6 (95%CI: 3.8-7.5) months were observed in patients receiving eribulin as first-, second-, and third-line therapy, respectively. In addition, median PFSs were 7.1 (95% CI: 5.1-9.3), 9.6 (95%CI: 3.6-15.7), 4.6 (95%CI: 4.6-4.6) and 5.8 (95%CI: 4.4-7.3) months for HR+/HER2-, HR+/HER2+, HR-/HER2+, and mTNBC patients, respectively. Other results from the subgroups analysis were shown in table. Common treatment-related toxicity was hematological toxicities including leukopenia (23%), neutropenia (17%), and thrombocytopenia (10%). There was no ≥grade 3 adverse events and no adverse event-related treatment discontinuation. Conclusions: Eribulin monotherapy or combined with targeted therapy was effective and well-tolerated as the first to third lines of treatment in ABC. This promising therapeutic outcome might warrant further studies in early eribulin administration in ABC patients. Clinical trial information: NCT04683445. [Table: see text]
Single center experience with alpelisib-fulvestrant in heavily pretreated women with HR(+), HER-2 (−) metastatic breast cancer.
Authors: Dimitrios Tryfonopoulos, Vasiliki Tzouda, Dionysia Zouki, Athina Kyriakidou, Evangelos Sarris, Anastasios Grivas, Panagiotis Gouveris, George Papaxoinis, Stamatina G Demiri
Journal: Journal of Clinical Oncology (2022)

e13034 Background: HR-positive, Her2-negative metastatic breast cancer patients harboring PIK3CA mutations are associated with resistance to endocrine therapy and worse prognosis. Results from the phase III SOLAR-1 trial demonstrate improved PFS for patients treated with Alpelisib-Fulvestrant after failure on first or second line treatment with aromatase inhibitor. Methods: Within an early access program for Alpelisib in a single oncology center, patients diagnosed with metastatic HR-positive, Her2 -negative breast cancer were screened for PIK3CA mutations. New generation sequencing (NGS) was the preferred technique to identify carriers with PIK3CA mutations on soft tissue or liquid biopsy. Patients who progressed and carried PIK3CA mutations received Alpelisib and fulvestrant as subsequent line of therapy. Results: Among 32 patients (pts) screened, 13 (40,6%) had a PIK3CA mutation. In total, 11 pts received alpelisib. Median age at diagnosis was 57.5 years (range, 39-69). Eight pts (72.7%) had been operated for early-stage breast cancer, 6 (54.5%) had received adjuvant chemotherapy and 5 (45.5%) had received adjuvant radiotherapy. Of 11 pts with evaluable histology, 3 pts (27.3%) had high grade tumors at diagnosis. Ten pts (90.9%) had PR positive tumors. Median Ki67 was 20% (range, 2-80). Eight pts (72.7%) had PIK3CA exon 20 and 3 (27.3%) had exon 9 mutations. Six pts (54.5%) had received prior chemotherapy in the metastatic setting and 10 (90.9%) prior CDK4/6 inhibitor. Three pts (27.3%) received Alpelisib as 2 nd line and all remaining patients received alpelisib beyond 3 rd line treatment. All pts (100%) had metastasis to the bones, 8 pts (72.7%) to the liver, 6 pts (54.5%) to the lungs and 2 pts (18.2%) to the brain. Until the date of last assessment, Alpelisib was administered for a median of 5.1 months (range, 0.4-21.3). Ten pts were evaluable for response to treatment with Alpelisib. One (10%) had CR, 5 (50%) SD and 4 (40%) PD as best response. Median duration of disease control was not reached. Baseline characteristics were not associated with disease control. Adverse events noticed were thrombocytopenia grade II (1/11), diarrhea grade II (2/11), skin rash grade I &amp;II (4/11), weakness grade III (1/11) and hyperglycemia (3/11). Conclusions: Prevalence of PIK3CA mutations is consistent with published data. Furthermore, combination of Alpelisib-Fulvestrant is a highly active line of therapy even in heavily pretreated patients.